1. Field of the Invention
This invention relates to erodible compositions suitable for pharmaceutical excipients and more particularly to erodible compositions suitable for use as excipients for drugs which are subject to supercooling.
2. Description of the Prior Art
In chemotherapy of diseases it is frequently desirable to maintain the concentration of the therapeutic drug at a relatively constant level in the blood or organ being treated. One method for achieving this goal is to administer the drug continuously at a rate which balances its rate of metabolism and/or excretion. In a hospital environment this goal can be attained by intravenously administering a drug, but outside of such an environment this method of administration is impractical in the great majority of cases. Consequently, the most common method of administering a drug is orally, in the form of tablets, capsules, and the like, which preferably have sustained release characteristics. The drug released therefrom is usually absorbed from the gastrointestinal tract and reaches the target organ via the blood stream.
Among the various types of sustained release dosage forms which have been developed are erodible matrices, i.e., dosage forms wherein the drug is entrapped in a matrix which upon ingestion gradually decomposes in the intestinal fluid thereby releasing the drug for absorption. An example of such a dosage form is found in Schmitt, U.S. Pat. No. 4,346,709, wherein the device comprises a drug dispersed in a bioerodible polymer which is a poly(orthoester) or a poly(orthocarbonate) containing an erosion rate modifier. The erosion rate modifiers of Schmitt are mono- and polybasic organic acids which adjust the pH at the surface of the erodible matrix to accelerate or retard the decomposition of the polymer in the gastric or intestinal environment.
In a further example, Sothmann, et al., in U.S. Pat. No. 4,351,825, disclose a sustained release oral dosage form wherein a drug is dispersed in a matrix of a water-insoluble polymethacrylate, e.g., a copolymer of acrylic and methacrylic acid esters containing quaternary ammonium groups or a copolymer of methacrylic acid and methyl methacrylate, which has an anionic character. The granules of the matrix material are mixed with the active drug and an erosion rate modifier which is an ester of a long chain fatty acid with glycerine or a long chain alcohol.
Additionally, Kleber, et al., in U.S. Pat. No. 4,333,919, disclose controlled release formulations comprised of a drug mixed with a copolymer of lactic and glycolic acids. The formulations may also contain adjuvants such as glyceryl distearate. The formulations are primarily intended for growth stimulants for ruminants. Accordingly, they are administered by filling open-ended steel cylinders with the formulations and placing the cylinders in the rumen of the animal. The filled steel cylinders remain in the rumen, and the growth stimulant is gradually released as the matrix is eroded by the rumen fluids.
It seems evident from these disclosures, and others, that the erodible formulations of the prior art have generally required specially prepared polymers, and that the rate of erosion of such polymers cannot always be adjusted to provide for preferential release of the drug in a particular portion of the gastrointestinal tract, e.g., in the stomach or small intestine.
Erodible matrix formulations based on mixtures of polyethylene glycols specially adapted for buccal dosage forms have been disclosed by Keith et al, U.S. Pat. No. 4,764,378. An erodible matrix suitable for preparing pharmaceutical dosage forms for oral administration is disclosed in U.S. Pat. No. 4,629,621, the grandparent application of this application. and in U.S. Pat. No. 4,774,074, a continuation-in-part of U.S. Pat. No. 4,629,621. The compositions of those U.S. Patents comprise a polyethylene glycol or mixture thereof in combination with an insoluble amphiphile. Preferred compositions incorporating particular insoluble amphiphiles are disclosed in U.S. Pat. No. 4,774,976, to Snipes and Wagner, a continuation-in-part of U.S. Pat. No. 4,629,621. Preferred erodible compositions based on a mixture of one or more polyethylene glycols and a polyethylene oxide-polypropylene oxide block copolymer in combination with an insoluble amphiphile are disclosed in U.S. patent application No. 06/918,273, the parent application of this application.
However, while the erodible compositions disclosed in the parent applications and related applications have been found to be useful as controlled release matrices for many pharmaceutical compounds, certain drugs have presented problems in formulation. It has been found that some drugs, particularly those having melting points not far above room temperature, have a tendency to supercool when the molten drug is cooled to solidify it. When a sample of such a drug is melted by heating and then cooled to a temperature below its melting point, the material does not immediately solidify, but rather remains liquid for some time. Although the drugs eventually solidify, their tendency to supercool causes a problem when they are incorporated into the matrices disclosed in the the parent applications and related applications. Inasmuch as the dosage forms disclosed in those applications are prepared by melting together the ingredients of the matrix, adding the drug to the molten matrix and cooling the mixture in a mold, the supercooling tendency of these drugs, especially when they are present in relatively large proportion in the composition of the dosage form, prevents the dosage form from solidifying properly. In addition, some drugs having comparatively high melting points dissolve to some extent in the molten matrix and cause the matrix itself to exhibit delayed solidification upon cooling. Evidently, dosage forms which have not solidified cannot be removed from the mold and subjected to the handling necessary to package them.
Therefore, a need has continued to exist for an erodible matrix, prepared from readily available materials which are suitable for sustained release pharmaceutical formulations, wherein the rate of erosion can be substantially controlled and which is capable of forming a solid mixture with drugs which are subject to supercooling.